Method of treating movement disorders using barbituric acid derivatives

ABSTRACT

A method of treating movement disorders comprises administering to a human or animal subject in need of treatment a therapeutically effective amount of at least one compound according to the following formula: 
                         
wherein R 3  and R 4  are each independently selected from the group consisting of lower alkyl, phenyl and lower alkyl substituted phenyl, and R 1  and R 2  are each independently either a hydrogen atom or a radical of the formula
 
                         
wherein R 5  and R 6  are each independently selected from the group consisting of H, lower alkyl, phenyl and lower alkyl substituted phenyl, its pharmaceutically acceptable salts, prodrugs, and metabolites thereof.

This application claims the benefit of prior U.S. ProvisionalApplication No. 60/432,470, filed Dec. 11, 2002, the entire contents ofwhich are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to the treatment of movement disorders,such as essential tremor, through the administration of one or more of5,5 diphenyl barbituric acid and derivatives thereof.

BACKGROUND OF THE INVENTION

Movement Disorders

Movement disorders include a wide variety of disease states andphysiological conditions. Non-limiting examples include variousdyskinesias such as tremor, dystonia, chorea, athetosis, tic disorders,blepharospasm, as well as hemiballysmus, myoclonus, focal dystonias,such as writer's cramp and torticollis, restless leg syndrome andasterixis. These excessive or otherwise abnormal involuntary movementsmay vary significantly in rate, frequency, periodicity andprogressionary character. Such movements may be seen in sometimesoverlapping disorders such as Parkinson's disease; essential tremor,a.k.a. benign tremor or familial tremor; tic disorders, e.g. Tourette'ssyndrome; idiopathic dystonia (inducing writer's cramp), progressivesupranuclear palsy and Wilson's disease. Movement disorders aredifferent from seizure disorders in that movement disorders are oftensuppressible, they often subside or are absent during sleep and aredistractable and not associated with the loss of consciousness.

Tremor is the most common of all movement disorders. Tremor is definedas an involuntary rhythmic, oscillatory movement about a joint producedby contractions of reciprocally innervated agonist/antagonist muscles,and is repetitive and regular in frequency. (Essential Tremor: APractical Guide to Evaluation, Diagnosis, and Treatment, Clinician, Vol.19 (No. 2), pgs. 1–15, 2001). It also ranks as one of the mostdebilitating symptoms in all of neurology. For example, the presence ofeven mild tremor in the upper extremities can make even the simplest oftasks impossible to perform. (Wasielewski P. G. et al., PharmacologicTreatment of Tremor, Movement Disorders, Vol. 13, Supplement 3, 1998, pp90–100). Essential tremor and tremor associated with Parkinson's diseaseare the most common types of tremor encountered in clinical practice.(Wasielewski P. G. et al., Pharmacologic Treatment of Tremor, MovementDisorders, Vol. 13, Supplement 3, 1998, pp 90–100).

Essential tremor is the most common form of tremor and of all movementdisorders and perhaps the most common primary neurological disorder.Estimates of the prevalence in the elderly population range from 1 to22%, with 1–2% being a conservative number. (Findley L. J., Epidemiologyand Genetics of Essential Tremor, Neurology, 2000, 54 (Suppl. 4),S8–S13). While often a minor problem and unassociated with other disease(hence the term “benign tremor or benign essential tremor”), it causessignificant motor impairment for many individuals. In its classic form,it is a tremor involving the upper extremities and/or the head. Usually,it has a frequency of 5–8 Hz, is absent with rest, presents with asustained posture and is not significantly exacerbated by movement.(Marsden C D. Origins of Normal and Pathological Tremor in MovementDisorders: Tremor. Eds. L. J. Findley and R. Capildeo, New York. OxfordUniversity Press, 1984, pp. 37–84).

The cause and pathophysiology of essential tremor remain unknown. Nopathologic substrate has been demonstrated in autopsy studies. Positronemission tomography (PET) studies of glucose metabolism and blood flowhave demonstrated only general findings of increased activity in thebrain stem (medulla), thalamus, cerebellum, striatum and sensorimotorcortex.

Parkinson's disease is a progressive disorder with a prevalence of 1–2%in people over the age of 50. It has a worldwide distribution and has nogender preference. Unlike essential tremor, untreated Parkinson'sdisease is life shortening. Symptoms of the disease include (1) shakingof the hands, arms, legs or feet while the patient is resting (theshaking may be more noticeable on one side of the body, and it mayaffect the hands more than the feet, the shaking often stops, however,as soon as the patient moves his limbs); (2) slowness of movement or abrief, temporary delay in movement; (3) difficulty in maintaining one'sbalance; (4) rigidity or stiffness of the patient's limbs; (5) facialmasking (a still facial expression with fewer blinks of the eyes); (6)difficulty in speech; (7) difficulty swallowing; and (8) chorea anddystonic posturing, particularly as a side effect of treatment withdopaminergic agents. As the Parkinson's disease progresses, patients maybe forced to work fewer hours and cut back on their activity level.Simple tasks become more of a challenge, and they may need some helpfrom family and friends. Patients may find that using a wheelchair helpsthem move around more easily, and they may need help with dailyactivities.

Current Treatment of Movement Disorders

1. Treatment of Essential Tremor

Alcohol remains the most effective single agent for treatment ofessential tremor. Estimates of patients responsive to alcohol range from50–90%. (Koller, W. C., Hristove, A., Brin, M. Pharmacologic Treatmentof Essential Tremor. Neurology 2000; 54 (Suppl 4), pp. S30–S38.) Itseffect may be dramatic in some individuals. However, the half-life ofalcohol is brief and the side effects are numerous.

Beta-adrenergic receptor blocking agents such as propranolol have alsobeen widely used for over 30 years. However, even when beneficial, theclinical response is variable and incomplete. Moreover, beta-adrenergicblockers are probably of no benefit in 50% or more of patients.

The anticonvulsant primidone has been demonstrated to be effective in asignificant subpopulation of patients. Comparative studies of primidoneand beta-blocking agents variously report either therapeutic equivalencyor slightly greater efficacy for primidone. Primidone, unlikebeta-blocking drugs, will completely suppress tremor in some patients.(Findley, L. J., Cleeves, L., Caletti, S. Primidone in Essential Tremorof the Hands and Head: A Double Blind Controlled Clinical Study. J.Neurol Neurosurg Psych, 1985, 48, pp. 911–915.) Primidone, however,produces a high incidence of side effects. Furthermore, primidone haslittle or no effect on head tremor, even in patients with a positiveresponse of the limbs. Primidone is converted into two activemetabolites, phenobarbital and phenylethylmalonamide (PEMA). PEMA hasbeen found to have no anti-tremor effect.

Phenobarbital has some anti-tremor effect, but not as prominent asprimidone or beta-blocking agents, particularly when the patients areassessed in terms of functional improvement. (Findley, L. J. ThePharmacology of Essential Tremor in Movement Disorders 2^(nd) Edition.Morsden, C. D., Fahn S, Longdong: Butterworths, 1987. As detailed below,phenobarbital has sedative effects and can suppress respiration.

There have been brief reports of newer anticonvulsant drugs,particularly gabapentin, providing a benefit in treatment of essentialtremor. (See Gironell, A., Kulisevsky, J., Lopez-Villegas, D.,Hernandez, G., Pascual-Sedano, B., A Randomized Placebo-ControlledComparative Trial of Gabapentin and Propanolol in Essential Tremor.Arch. Neurol., 1999, 56, pp. 475–480.) None of these other agents,however, have gained wide use for this indication, presumably because oftheir neurological side effects and/or limited efficacy. Methazolamide,a carbonic anhydrase inhibitor, has been reported to be of some benefit.(Meunter, M. D., Daube, J. R., Caviness, J. N., Miller, P. M. Treatmentof Essential Tremor with Methazolamide. Mayo Clinic Proc, 1991, 66, pp.991–997.) However, primidone and propranolol are the only twoprescription drugs with proven efficacy in general clinical practice.Louis, E. D., N. Eng. J. Med., 345, (12), 2001, pp. 887–891.

U.S. Pat. No. 6,281,207 to Richter et al. discloses methods of combatingmovement disorders such as tremor by administering mirtazapine.

Surgical treatment of severe disabling essential tremor is sometimesuseful. This has most commonly involved thalamotomy (lesioning of thethalamus) and, more recently, the use of surgically implantedelectrodes. These procedures however have considerable potentialmorbidity.

Therefore, there exists a need for a method of treating essential tremorand other movement disorders having minimal adverse side effects, hightolerance, and significant effectiveness.

2. Treatment of Parkinson's Disease

The most widely recognized drug for the treatment of Parkinson's diseaseis levodopa, a medication that is converted into dopamine when itcrosses into the brain. Levodopa reduces the symptoms of this diseasebecause dopamine is the chemical that is necessary for human muscles tofunction normally. It is called a replacement drug because it replacesdopamine. For most patients with Parkinson's disease, levodopa providessignificant improvement in many symptoms, including tremor. However, thetherapeutic benefits of this drug usually last for only a limited periodof time. After about 3 to 5 years of treatment, levodopa becomes lesseffective in reducing symptoms in most patients. At times the patientcan move around easily or with slight tremor and rigidity, and at othertimes the patient has difficulty with movement, as if the medicine is“wearing off.” For this reason, doctors try to keep the dose of levodopaas low as possible or may not begin treatment with levodopa until thesymptoms can no longer be managed by other means. (Lang, A. E. et al.,N. Eng. J. Med., 339 (16), 1998, pp. 1130–1143).

The side effects of levodopa include nausea, vomiting, loss of appetite,rapid heart rate, and lowered blood pressure when a person stands from asitting position. To reduce these side effects, levodopa is oftenprescribed in combination with carbidopa, and this drug combination ismarketed under the trademark Sinemet™ (Bristol-Myers Squibb). Thecarbidopa in Sinemet™ prevents levodopa from being metabolized in thestomach and liver, so more of the levodopa can get to the brain, whichpermits administration of a smaller dose of levodopa or alternativelyincreases the effectiveness of a given administered dose of levodopa.Even though carbidopa helps to reduce the side effects of levodopa, manypatients who take Sinemet™ may still experience nausea, vomiting, andloss of appetite when they begin taking it or after their dosage isincreased. Other side effects of carbidopa/levodopa combinationmedications include dry mouth, daytime sleepiness, nervousness, vividdreams, insomnia, and a form of motor fluctuation called dyskinesia,characterized by involuntary writhing movements. Sometimes dyskinesiaresults when the dosage of the medication is too high.

Another group of medications for Parkinson's Disease is dopamineagonists. Dopamine agonists are drugs that stimulate the parts of thehuman brain that normally respond to dopamine. In effect, the brain“thinks” it is receiving dopamine, so these drugs help satisfy thebrain's need for dopamine. The most commonly used dopamine agonists inthe United States include Parlodel™ (bromocriptine, Novartis), Permax™(pergolide mesylate, Amarin), MIRAPEX™ (pramipexole hydrochloride,Pharmacia & Upjohn) and Requip™ (ropinirole, GlaxoSmithKline). Parlodel™and Permax™ are synthetic derivatives of a chemical called “ergot”. Theside effects are similar to those of levodopa: nausea, vomiting,confusion, hallucinations, lightheadedness and fainting. A rare sideeffect known as fibrosis (membrane lining of body organs can becomethickened or scarred) has also been reported. MIRAPEX™ has been shown tobe effective in treating the symptoms of early disease without levodopa.During the advanced stages, taking MIRAPEX™ in combination with levodopamay reduce the dose of levodopa that is needed. The use of MIRAPEX™ cancause drowsiness and the possibility of suddenly falling asleep duringdaily activities, which could result in an accident while driving. Themost common side effects of MIRAPEX™ are nausea, sleeplessness,constipation, involuntary movement, sleepiness, dizziness upon standing,and hallucinations.

Another group of medications for Parkinson's Disease iscatechol-O-methyltransferase (COMT) inhibitors (e.g., Tasmar™(tolcapone, Roche Laboratories) and Comtan™ (entacapone, Novartis)).COMT is one of two enzymes that break down levodopa before the brainconverts it into dopamine. When the COMT enzyme is blocked by the COMTinhibitors, dopamine stays in the brain for a longer period of time.COMT inhibitors are usually taken with levodopa. The most common sideeffects reported by patients who have taken COMT inhibitors includeunusually vivid dreams or visual hallucinations, nausea, difficulty insleeping, daytime drowsiness, headache, and excessive involuntarymovements. In addition, in 1998 the U.S. Food and Drug Administrationreported that Tasmar™ can cause liver damage, so now doctors are advisedto monitor their patients who are taking this drug on a regular basis tomake sure their liver is functioning normally.

Anticholinergics have also been used in the treatment of Parkinson'sdisease. Before doctors begin treating Parkinson's disease patients withlevodopa, they may prescribe anticholinergic drugs such as Artane™ torelieve symptoms. When the brain cannot get enough dopamine, it producesincreased quantities of a chemical called acetylcholine, and too muchacetylcholine causes tremor and rigidity in patients. Anticholinergicdrugs block the effect of acetylcholine, so they are effective inreducing tremor and rigidity in patients. Anticholinergics are notusually prescribed for long periods of time because of the side effectsthey cause in patients, which include dry mouth, blurred vision,constipation, difficulty in urinating, confusion, and hallucinations.

Dopamine is broken down in the brain by an enzyme called monoamineoxidase (MAO). Hence, selegiline and other MAO inhibitors help the brainmake the most of the dopamine that is still being produced and/ordopamine that is being supplied to the brain by other drugs. When aParkinson's disease patient takes an MAO inhibitor, it slows down theprogress of this enzyme, which increases the amount of dopamine that isavailable to the brain. The side effects of selegiline includeheartburn, loss of appetite, nausea, dry mouth, dizziness, constipation,and insomnia.

Anti-viral agents such as Symmetrel™ (amantadine, Endo Labs) providemild relief of Parkinson's symptoms in newly-diagnosed patients. It hasbeen used to treat this disease for many years, but even today, medicalresearchers and doctors aren't really sure how it works in the humanbrain. Unfortunately, it tends to cause insomnia and daytime fatigue,and other side effects that have been reported include red or purpleskin blotches (often on the patient's legs), swelling of the feet,anxiety, dizziness, difficulty in urinating, and hallucinations. (Lang,A. E. et al., N. Eng. J Med., 339 (16), 1998, pp. 1130–1143).

U.S. Pat. No. 6,281,207 to Richter et al. discloses methods of combatingmovement disorder such as Parkinson's disease by administeringmirtazapine.

Surgery can dramatically reduce symptoms for some patients in theadvanced stages of Parkinson's disease. Doctors may suggest surgery asan option for such patients because they have been taking combinationsof drugs over a long period of time, and those drugs have become lessand less effective. A pallidectomy or pallidotomy is a surgicalprocedure in which a lesion is created in a specific area of the brain(globus pallidus) to help restore the balance required for normalmotion. The majority of patients who have had this surgery have gainedimmediate, significant improvements in their ability to function, andthose benefits have lasted for at least a year. Deep brain stimulation(DBS) has also been used by physicians as a preferred alternative to apallidotomy. Although these surgical approaches have produced somedesirable results, the long-term effects of such surgeries forParkinson's patients are not yet known. Therefore, doctors generallyreserve these as last resort treatments for their patients. (Lang, A. E.et al., N. Eng. J Med., 339 (16), 1998, pp. 1130–1143).

In view of the above, there exists a need for a method of treatingmovement disorders that are either symptoms of or associated withParkinson's disease or not using an active agent having minimal adverseside effects, high tolerance, and significant effectiveness.

Barbituric Acid Derivatives

1. Sedating Barbituric Acid Derivatives

Barbiturates (or barbituric acid derivatives) have been developed andhave been used as the primary drugs for the treatment of insomnia formany years. Barbiturates depress both the respiratory drive and themechanisms responsible for the rhythmic character of respiration.(Goodman & Gilman's, The Pharmacological Basis of Therapeutics, Chapter17, 9^(th) Edition, McGraw-Hill). They have been implicated in thousandsof deaths due to accidental (or deliberate) ingestion (resulting inhomicide, suicide or accidental death) since they are associated withserious, often fatal, central nervous system (CNS) depressive effectsfollowing acute overdosage. Barbiturates have been chronically abused bya substantial portion of the population. When coadministered with otherdrugs, barbituatates may interact with them with a potentially lethaloutcome. Currently or previously clinically employed barbituratesinclude amobarbital, barbital, butabarbital, and hexobarbital,mephobarbital, pentobarbital, phenobarbital, secobarbital, thiamylal,and thiopental. Barbiturates with a short to intermediate duration ofaction (e.g., amobarbital, butabarbital, pentobarbital, secobarbital,and vibarbital) are used as sedative-hypnotics. Phenobarbital is used asan anticonvulsant for the treatment of seizure disorders.Ultrashort-acting barbiturates (e.g., thiamylal and thiopental) can beused as anesthetics. (Craig, C. R. and Stitzel R. E., ModernPharmacology, Chapter IV, 2^(nd) Edition, 1986, Little, Brown andCompany, Boston/Toronto).

As mentioned above, sedative barbiturates such as phenobarbital havebeen found to have some anti-tremor effect. However, its effectivenessis severely limited by its strong side effects.

2. Non-Sedating Barbituric Acid Derivatives

U.S. Pat. No. 4,628,056 (“the '056 Patent”) to Levitt et al. disclosesnovel oxopyrimidine derivatives of the general formula

wherein R₁ and R₂ may be the same or different and are each hydrogen orlower alkyl optionally substituted by lower alkoxy, and R₃ and R₄ may bethe same or different and are each phenyl optionally substituted bylower alkyl or halogen, provided that when R₁ and R₂ are both hydrogen,R₃ and R₄ are each substituted phenyl. The '056 Patent discloses thatthese compounds are useful as anticonvulsants, and antianxiety agentsand as muscle relaxants. According to the '056 Patent, animals givensuch compounds continue to behave normally and do not show anyobservable effects on locomotion, escape behavior or feeding behavior.The '056 Patent further elaborates that the compounds disclosed thereinare useful in treating mammals for strain and stress conditions andnervous dysfunctions such as convulsions, seizure, muscle stiffness,nervous strain and anxiety. The '056 Patent does not mention or suggestthat such compounds can be used to treat any movement disorders.

U.S. Pat. No. 6,093,820 (“the '820 Patent”) to Gutman et al. disclosesthat alkoxyalkylated ureide compounds such as N-methoxymethylethosuximide, N-methoxymethyl glutethimide, andN-methoxymethyl-5,5-diphenylbarbituric acid are also useful in treatingconvulsions, seizures, muscle stiffness, or anxiety. Again, the '820Patent doses not mention or suggest that any of these compounds can beused to treat any movement disorders.

SUMMARY OF THE INVENTION

The present invention provides a method of treating movement disorderscomprising administering an amount effective for that purpose of atleast one compound according to the following formula (I):

wherein R₃ and R₄ are each independently selected from the groupconsisting of lower alkyl, phenyl and lower alkyl substituted phenyl,and R₁ and R₂ are each independently either a hydrogen atom or a radicalof the formula

wherein R₅ and R₆ are each independently selected from the groupconsisting of H, lower alkyl, phenyl and lower alkyl substituted phenyl;

or a pharmaceutically acceptable salt, prodrug or metabolite thereof.

In one embodiment, the movement disorder treated with one or more of theforegoing compounds is essential tremor.

In another embodiment, the movement disorder is tremor and/or dystoniaor chorea associated with Parkinson's disease.

In yet another embodiment, the movement disorder is not associated withParkinson's disease.

In a further embodiment, the movement disorder is a focal dsytonia, suchas writer's cramp.

In yet a further embodiment, the movement disorder is restless legsyndrome.

According to a preferred embodiment of the present invention, a methodof treating essential tremor comprises administering an amount effectivefor that purpose of at least one compound according to the followingformula (II):

or a pharmaceutically acceptable salt, prodrug or metabolite thereof.

According to another preferred embodiment of the present invention, amethod of treating essential tremor comprises administering an amounteffective for that purpose of at least one compound according to thefollowing formula (III):

or a pharmaceutically acceptable salt, prodrug or metabolite thereof.

According to a further preferred embodiment of the present invention, amethod of treating essential tremor comprises administering an amounteffective for that purpose of at least one compound according to thefollowing formula (IV):

or a pharmaceutically acceptable salt, prodrug or metabolite thereof.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the mean absolute change in baseline tremor score andplasma concentrations of DMMDBP, MMMDPB, and DPB after multiple oraldoses of placebo or DMMDBP in patients with essential tremor, observedduring the study set forth in Example 2.

FIG. 2 shows the mean absolute change in baseline tremor score vs.plasma concentrations of MMDPB and DPB after multiple oral doses ofDMMDPB in patients with essential tremor, observed during the study setforth in Example 2.

DETAILED DESCRIPTION OF THE INVENTION

In describing particular embodiments of the present invention, specificterminology is employed for the sake of clarity. However, the inventionis not intended to be limited to the specific terminology so selected,and it is to be understood that each specific element includes alltechnical equivalents which operate in a similar manner to accomplish asimilar purpose. Nevertheless, certain terms are given specialdefinitions, as follows:

The term “combination” applied to active ingredients is used herein todefine a single pharmaceutical composition (formulation) comprising atleast two active ingredients or two or more separate pharmaceuticalcompositions (formulations), each comprising at least one activeingredient, said separate formulations to be administered conjointly.

The term “conjoint administration” and its variants (e.g., “administeredconjointly”) is used to refer to administration of two or more activeingredients simultaneously in one composition, or simultaneously indifferent compositions, or sequentially. For the sequentialadministration to be considered “conjoint,” however, the activeingredients should be administered separated by no more than a timeinterval that still permits the resultant beneficial effect fortreating, preventing, arresting, delaying the onset of and/or reducingthe risk of developing a movement disorder. For example, the activeingredients should be administered on the same day (e.g., each—once ortwice daily), preferably within an hour of each other, and mostpreferably simultaneously.

The term “treat” and its variants (e.g., “treatment”, “treating”) isused herein to mean to relieve, alleviate or eliminate at least onesymptom of a disease in a subject. For example, in relation to tremor,the term “treat” means to reduce or to eliminate tremor or to decreaseits intensity or to improve impairment of coordination associated withtremor. Such reduction or decrease should be measurable or perceptibleto the physician attending the patient.

The present invention aims to provide a method for treating movementdisorders such as essential tremor or Parkinson's disease. Morespecifically, it aims to treat movement disorders effectively andwithout the severe risks and/or side effects often associated with othertreatment modalities, or with a significantly reduced number of suchside effects and/or risks. Such risks and side effects include but arenot limited to sedation, danger of overdose, and respiratory arrest.

Cyclic ureides having the following general formula (I):

wherein R₃ and R₄ are each independently selected from the groupconsisting of lower alkyl, phenyl and lower alkyl substituted phenyl,and R₁ and R₂ are each independently either a hydrogen atom or a radicalof the formula

wherein R₅ and R₆ are each independently selected from the groupconsisting of H, lower alkyl, phenyl and lower alkyl substituted phenyl,its pharmaceutically acceptable salts, metabolites, and prodrugs thereofare useful in the treatment of movement disorders, especially essentialtremor, tremor or other movement disorder associated with Parkinson'sdisease, focal dystonias, writer's cramp or restless leg syndrome or anyof the other movement disorders enumerated above.

One preferred type of cyclic ureides useful in the method of the presentinvention are barbituric acid derivatives disubstituted at the5-position. Another preferred embodiment of the present invention uses5,5-diphenyl barbituric acid and derivatives for the treatment ofmovement disorders. Specific preferred compounds useful in the treatmentmethod of the present invention include N,N-dimethoxymethyl diphenylbarbituric acid (DMMDPB), monomethoxymethyl diphenyl barbituric acid(MMMDPB) and diphenyl barbituric acid (DPB), and pharmaceuticallyacceptable salts and prodrugs thereof.

Compounds useful in the treatment method of the present invention can bemade by any known synthetic technique. By way of illustration, U.S. Pat.Nos. 4,628,056 and 6,093,820, herein incorporated in their entirety byreference, disclose examples of such methods for the preparation ofcompounds used in the present invention. A preferred pathway for makingMMMDPB is set forth in Example 1.

Compounds useful in the treatment method of the present invention may beformulated into compositions or formulations that additionally andoptionally comprise any suitable adjuvants, excipients, additives,carriers, solvents, additional therapeutic agents (e.g., for conjointuse as a combination treatment, including for example one or moreadditional agents for combating the movement disorder and/or aconcurrrent physiological condition), bioavailability enhancers,side-effect suppressing constituents, or other ingredients that do notadversely affect the efficacy of the composition for combating movementdisorders.

Pharmaceutically acceptable salts of the movement disorder-combatingcompounds of the invention and physiologically functional derivativesthereof include salts derived from an appropriate base, such as analkali metal (for example, sodium, potassium), an alkaline earth metal(for example, calcium, magnesium), ammonium and NX₄ ⁺ (wherein X isC₁–C₄ alkyl). Pharmaceutically acceptable salts of an amino groupinclude salts of organic carboxylic acids, such as tartaric, aliphatic,cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classesof organic acids, such as, for example, formic, glucuronic, malic,maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,mesylic, salicylic, hydroxybenzoic, phenylacetic, mandelic, embonic(pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic, stearic, algenic,hydroxybutyric, cyclochexylaminosulfonic, galactaric and galacturonicacid and the like, lactobionic, fumaric, and succinic acids; organicsulfonic acids, such as methaniesulfolic, ethanesulfonic, isothionic,benzenylesulfonic and p-toluenesulfonic acids; and inorganic acids suchas hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric,sulfamic and phosphoric acid and the like. Pharmaceutically acceptablesalts of a compound having a hydroxy group consist of the anion of saidcompound in combination with a suitable cation such as Na⁺, NH₄ ⁺ or NX₄⁺ (wherein X is, for example, a C₁–C₄ alkyl group), Ca⁺⁺, Li⁺, Mg⁺⁺, or,K⁺ and zinc or organic salts made from primary, secondary and tertiaryamines, cyclic amines, N,N′-dibenzylethylenediamine, chloroprocaine,choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine)and procaine and the like. All of these salts may be prepared byconventional means from the corresponding compound by reacting, forexample, the appropriate acid or base with the compound in free form.

For use in treatments describes herein, salts of movementdisorder-combating compounds of the invention will be pharmaceuticallyacceptable, i.e., they will be salts derived from a pharmaceuticallyacceptable acid or base. However, salts of acids or bases which are notpharmaceutically acceptable may also find use, for example, in thepreparation or purification of a pharmaceutically acceptable compound.All salts, whether or not derived from a pharmaceutically acceptableacid or base, are within the scope of the present invention. Prodrugsand active metabolites of compounds disclosed herein are also within thescope of the invention.

Prodrugs

A prodrug is a pharmacologically active or more typically an inactivecompound that is converted into a pharmacologically active agent by ametabolic transformation. In vivo, a prodrug readily undergoes chemicalchanges under physiological conditions (e.g., are acted on by naturallyoccurring enzyme(s)) resulting in liberation of the pharmacologicallyactive agent. Prodrugs may be administered in the same manner as theactive ingredient to which they convert or they may be delivered in areservoir form, e.g., a transdermal patch or other reservoir which isadapted to permit (by provision of an enzyme or other appropriatereagent) conversion of a prodrug to the active ingredient slowly overtime, and delivery of the active ingredient to the patient.

Suitable prodrugs of MMDPB include, but are not limited to, mono- anddi-phosphate and mono and di-phosphonooxyalkyl derivatives of MMDPB.Preferred prodrugs are the mono- and di-phosphonooxymethyl derivatives.

An exemplary method for synthesis of the prodrugs involves aderivatizing agent represented by the formula shown below:

wherein A is any leaving group that is displaced by a nucleophilictertiary amine group in the compounds of the present invention. Suitableexamples of the leaving group A include, but are not limited to,tosylate, triflate, iodine, bromine, chlorine, acetate and hydroxyl.Further discussion of suitable leaving groups may be found in Hatshom,S. R., Aliphatic Nucelophilic Substitution, Cambridge University Press,1973.

R₇ and R₈ independently represent any suitable organic or inorganicresidue, such as, but not limited to, straight chain or branched alkyl,such as methyl, ethyl, propyl, etc., an aromatic group, such as benzylor phenyl, a cyclic hydrocarbon, such as cyclohexane, or any of theabove substituted with one or more heteroatoms, such as S, N, or O.

Each Y independently represents a phosphate protecting group, such as,but not limited to, methyl, ethyl, tertiary butyl, benzyl, isopropyl, ormore generally lower (C₁–C₄) alkyl or benzyl. Other suitable examples ofphosphate protecting groups may be found in Green T. W., et al.,Protective Groups In Organic Synthesis, 2^(nd) Ed., Wiley, New York,1991.

Synthesis of suitable prodrugs may be envisaged according to the schemeshown below:

wherein R₁, R₂, R₃, and R₄ are as described above.

An alternate synthesis of the prodrugs is shown in the scheme below.

wherein W and Z are leaving groups similar to A, and can be the same ordifferent. T is any organic or inorganic cationic species. Suitablereaction conditions for synthesis of the prodrugs are set forth in U.S.Pat. No. 5,985,856, which is hereby incorporated by reference in itsentirety. The following are non-limiting examples of prodrugsspecifically contemplated for use in the present invention:

Additional prodrugs may readily be made by reacting a hydroxy derivativeof one of the compounds of the present invention with an activated aminoacyl, hemisuccinyl or acyl group to yield a prodrug ester.Alternatively, the hydroxy derivative can be reacted with halo alkylesters or with bis alkanoyl acetals or condensed with acetic anhydrideto yield additional prodrugs. See also U.S. Pat. Nos. 4,260,769 and3,679,683, which are hereby incorporated by reference in theirentireties.

Active Metabolites

An active metabolite is a compound which results from metabolism ofanother compound after administration of the latter to a subject.Metabolites can be identified by techniques well-known in the art.Examples of active metabolites are MMMDPB and DPB, each of which isgenerated in the recipient of DMMDPB. Conversely, each of MMMDPB andDMMDPB is a prodrug for DPB, and DMMDPB is a prodrug for MMMDPB.

The present invention also contemplates the treatment of movementdisorders using pharmaceutical dosage forms containing at least onecompound of the following formula:

or a pharmaceutically acceptable salt, metabolite, or prodrug thereof,wherein R₁, R₂, R₃ and R₄ are as described, supra, both for veterinaryand for human medical use.

In such pharmaceutical dosage forms, the active agent preferably isutilized together with one or more pharmaceutically acceptablecarrier(s) therefore and optionally any other therapeutic ingredients.The carrier(s) must be pharmaceutically acceptable in the sense of beingcompatible with the other ingredients of the formulation and not undulydeleterious to the recipient thereof.

A subject in whom administration of the therapeutic compound is aneffective therapeutic regimen for a disease or disorder is preferably amammal, more preferably a human, but can be any animal, including alaboratory animal in the context of a clinical trial or screening oractivity experiment employing an animal model. Thus, as can be readilyappreciated by one of ordinary skill in the art, the methods andcompositions of the present invention are particularly suited toadministration to any animal, particularly a mammal, and including, butby no means limited to, domestic animals, such as feline or caninesubjects, farm animals, such as but not limited to bovine, equine,caprine, ovine, and porcine subjects, research animals, such as mice,rats, rabbits, goats, sheep, pigs, dogs, cats, etc., avian species, suchas chickens, turkeys, songbirds, etc., i.e., for veterinary medical use.

Depending on the specific movement disorder to be treated, a suitabletherapeutically effective and safe dosage, as may readily be determinedwithin the skill of the art, and without undue experimentation, maybeadministered to subjects.

Effective Amounts

In general, while the effective dosage of compounds of the invention fortherapeutic use in accordance with the inventions may be widely varied,depending on the specific application, movement disorder, orphysiological state involved, as readily determinable within the skillof the art, suitable effective doses of the compounds and compositionsdescribed herein, and for achievement of a benefit in treatment, willbroadly be in the range of 10 micrograms (μg) to 150 milligrams (mg) perkilogram body weight of the subject per day, preferably in the range of50 μg to 130 mg per kilogram body weight per day, and most preferably inthe range of 100 μg to 120 mg per kilogram body weight per day. Thedesired dose may be presented as one or more sub-dose(s) administered atappropriate intervals throughout the day, or alternatively in a singledose, preferably for morning or evening administration. These dailydoses or sub-doses may be administered in unit dosage forms, forexample, containing from about 150 mg to about 1500 mg, preferably fromabout 200 mg to about 1200 mg, more preferably from about 250 mg toabout 850 mg, and most preferably about 450 mg of active ingredient perunit dosage form to be administered daily or twice daily. In specificembodiments, the daily dosage is equal to or greater than about 200,250, 300, 350, 400, 450 mg of active ingredient per unit dosage form tobe administered daily or twice daily. Typically, less than about 1500 mgof active ingredient of active ingredient per unit dosage form orpreferably less than about 1200 mg is to be administered daily.Alternatively, if the condition of the recipient so requires, the dosesmay be administered as a continuous or pulsatile infusion. The durationof treatment may be decades, years, months, weeks, or days, as long asthe benefits persist.

It is appreciated that the effective dose(s) may vary depending on thepatient's age, sex, physical condition, duration and severity ofsymptoms, duration and severity of the underlying disease or disorder ifany, and responsiveness to the administered compound. Accordingly, theforegoing ranges are guidelines and subject to optimization, and becauseof the good tolerability and low toxicity of the compounds of thepresent invention, higher doses may be administered. Effectiveness of adose can be assessed using e.g., the criteria described in Fahn S. etal., Clinical rating scale for tremor, In: Parkinson's Disease andMovement Disorders, Jancovic J., Tolosa E. (Eds.) 1998 Urban &Swarzenberg, Inc. Baltimore, Md., USA 225–234, this section beingincorporated by reference.

The mode of administration and dosage forms is closely related to thetherapeutic amounts of the compounds or compositions which are desirableand efficacious for the given treatment application.

Suitable dosage forms include but are not limited to oral, rectal,sub-lingual, mucosal, nasal, ophthalmic, subcutaneous, intramuscular,intravenous, transdermal, spinal, intrathecal, intra-articular,intra-arterial, sub-arachinoid, bronchial, lymphatic, and intra-uterilleadministration, and other dosage forms for systemic delivery of activeingredients. Formulations suitable for oral administration arepreferred.

To prepare such pharmaceutical dosage forms, one or more of theaforementioned compounds of formula (I) are intimately admixed with apharmaceutical carrier according to conventional pharmaceuticalcompounding techniques. The carrier may take a wide variety of formsdepending on the form of preparation desired for administration.

In preparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed. Thus, for liquid oralpreparations, such as, for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like. For solidoral preparations such as, for example, powders, capsules and tablets,suitable carriers and additives include starches, sugars, diluents,granulating agents, lubricants, binders, disintegrating agents and thelike. Due to their ease in administration, tablets and capsulesrepresent the most advantageous oral dosage unit form. If desired,tablets may be sugar coated or enteric coated by standard techniques.

For parenteral formulations, the carrier will usually comprise sterilewater, though other ingredients, for example, ingredients that aidsolubility or for preservation, may be included. Injectable solutionsmay also be prepared in which case appropriate stabilizing agents may beemployed.

In some applications, it may be advantageous to utilize the active agentin a “vectorized” form, such as by encapsulation of the active agent ina liposome or other encapsulant medium, or by fixation of the activeagent, e.g., by covalent bonding, chelation, or associativecoordination, on a suitable biomolecule, such as those selected fromproteins, lipoproteins, glycoproteins, and polysaccharides.

Treatment methods of the present invention using formulations suitablefor oral administration may be presented as discrete units such ascapsules, cachets, tablets, or lozenges, each containing a predeterminedamount of the active ingredient as a powder or granules. Optionally, asuspension in an aqueous liquor or a non-aqueous liquid may be employed,such as a syrup, an elixir, an emulsion, or a draught.

A tablet may be made by compression or molding, or wet granulation,optionally with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing in a suitable machine, with the activecompound being in a free-flowing form such as a powder or granules whichoptionally is mixed with a binder, disintegrant, lubricant, inertdiluent, surface active agent, or discharging agent. Molded tabletscomprised of a mixture of the powdered active compound with a suitablecarrier may be made by molding in a suitable machine.

A syrup may be made by adding the active compound to a concentratedaqueous solution of a sugar, for example sucrose, to which may also beadded any accessory ingredient(s). Such accessory ingredient(s) mayinclude flavorings, suitable preservative, agents to retardcrystallization of the sugar, and agents to increase the solubility ofany other ingredient, such as a polyhydroxy alcohol, for exampleglycerol or sorbitol.

Formulations suitable for parenteral administration usually comprise asterile aqueous preparation of the active compound, which preferably isisotonic with the blood of the recipient (e.g., physiological salinesolution). Such formulations may include suspending agents andthickening agents and liposomes or other microparticulate systems whichare designed to target the compound to blood components or one or moreorgans. The formulations may be presented in unit-dose or multi-doseform.

Parenteral administration may comprise any suitable form of systemicdelivery or delivery directly to the CNS. Administration may for examplebe intravenous, intra-arterial, intrathecal, intramuscular,subcutaneous, intramuscular, intra-abdominal (e.g., intraperitoneal),etc., and may be effected by infusion pumps (external or implantable) orany other suitable means appropriate to the desired administrationmodality.

Nasal and other mucosal spray formulations (e.g. inhalable forms) cancomprise purified aqueous solutions of the active compounds withpreservative agents and isotonic agents. Such formulations arepreferably adjusted to a pH and isotonic state compatible with the nasalor other mucous membranes. Alternatively, they can be in the form offinely divided solid powders suspended in a gas carrier. Suchformulations may be delivered by any suitable means or method, e.g., bynebulizer, atomizer, metered dose inhaler, or the like.

Formulations for rectal administration may be presented as a suppositorywith a suitable carrier such as cocoa butter, hydrogenated fats, orhydrogenated fatty carboxylic acids.

Transdermal formulations may be prepared by incorporating the activeagent in a thixotropic or gelatinous carrier such as a cellulosicmedium, e.g., methyl cellulose or hydroxyethyl cellulose, with theresulting formulation then being packed in a transdermal device adaptedto be secured in dermal contact with the skin of a wearer.

In addition to the aforementioned ingredients, formulations of thisinvention may further include one or more accessory ingredient(s)selected from diluents, buffers, flavoring agents, binders,disintegrants, surface active agents, thickeners, lubricants,preservatives (including antioxidants), and the like.

The formulation of the present invention can have immediate release,sustained release, delayed-onset release or any other release profileknown to one skilled in the art.

Pharmacokinetic studies of DMMDPB suggest that in humans the drug israpidly metabolized to MMMDPB and then slowly metabolized to DPB. DBPhas been shown to exert anticonvulsant properties in several animalmodels of seizure activity. (However, the present inventor hasindications that in movement disorders MMMDPB may be active itself.) Inany event, the administration of DMMDPB results in a sustained source ofDPB, which has been shown to provide prolonged anticonvulsant activity.

DMMDPB, is a member of a class of nonsedating barbiturate compounds. Ithas been demonstrated in animal models to retain the anticonvulsantproperties of phenobarbitol ('056 Patent). Thus, it offers thepossibility of a broad spectrum, barbiturate anticonvulsant without thedose limiting side effect of sedation. By eliminating sedation, and thusincreasing the tolerable dose, DMMDPB further offers the possibility ofa more effective anticonvulsant by virtue of enabling the use of higherdosages. It is anticipated that these beneficial properties persist whenthis compound (or its metabolite e.g., MMMDPB and DPB) is used to treatmovement disorders.

DMMDPB is a pro-drug and is converted to MMMDPB which in turn isconverted to DPB, an active metabolite of DMMDPB. The latter conversionhas been observed in both rats and dogs in addition to humans. DPB is amember of the barbituric class, which appears to possess anti-convulsantactivity without the sedative hypnotic properties of some barbiturates.It has a shorter time course of action than DMMDPB. Pharmacokineticstudies in man indicate that DPB has an elimination half-life of theorder of 55 hours, suggesting that DMMDPB could be administered oncedaily with a favorable impact on patient compliance. This informationhas relevance in the treatment of movement disorders.

There has been a substantial body of scientific work investigating theeffect of DPB in animals. DPB exerts anti-convulsant properties inseveral animal models of seizure activity. The utilization of DMMDPBresults in a sustained source of DPB, which provides prolongedanti-convulsant activity.

To assess safety in man and obtain pharmacokinetic information, a PhaseI single dose study was performed in a total of 64 healthy malesubjects. 48 subjects received DMMDPB and 16 subjects received placebo.All 64 subjects successfully completed the study. The subjects werehealthy, non-smoking males between 18 and 55 years of age. The doses ofDMMDPB administered orally in capsules were either 25 mg, 50 mg, 100 mg,200 mg, 400 mg, 600 mg, 900 mg or 1200 mg under fed conditions (high fatbreakfast).

DMMDPB, MMMDPB and DPB pharmacokinetics showed near linearity betweenadministered dose and measured plasma levels up to 1200 mg. Noneurological changes were observed. DMMDPB had no clear effect oncognitive or psychomotor functions with increasing dose.

A Phase I multiple dose clinical study was performed in a total of 40healthy male subjects. 30 subjects received DMMDPB and 10 subjectsreceived placebo. All 40 subjects successfully completed the study. Thesubjects were healthy, non-smoking males between 18 and 55 years of age.To each subject a total of 16 doses of DMMDPB were administered orally,a single dose in week one, followed by twice daily dosing for one week.Doses were either 150 mg, 200 mg, 300 mg, 450 mg or 600 mg under fedconditions.

DMMDPB was well tolerated. Minor adverse events were observed that alsooccurred with the placebo subjects. DMMDPB, MMMDPB and DPBpharmacokinetics showed near linearity up to 600 mg. Minimum plasmaconcentrations of DMMDPB, MMMDPB and DPB on Days 13, 14 and 15neurological changes were observed. DMMDPB had no clear effect oncognitive or psychomotor functions with increasing dose.

A Phase I clinical study was performed in a total of 16 healthy malesubjects. 12 subjects received DMMDPB and 4 subjects received placebo.15 subjects successfully completed the study. The subjects were healthy,non-smoking males between 18 and 55 ye ars of age. A total of 28 dosesof DMMDPB were administered orally, given twice daily for two weeks.Doses were either 450 mg or 600 mg under fed conditions.

DMMDPB was well tolerated. Minor adverse events were observed that alsooccurred with the placebo subjects. DMMDPB, MMMDPB and DPBpharmacokinetics showed near linearity up to 600 mg. Minimum plasmaconcentrations of DMMDPB, MMMDPB and DPB on Days 13, 14 and 15 indicatethat steady-state (DMMDPB, MMMDPB) and near steady-state (DPB) wasachieved with 14 days of dosing (28 doses). No neurological changes wereobserved. DMMDPB had little or no effect on cognitive or psychomotorfunctions.

It is expected that treatment with non-sedating barbiturates may beeffective for therapy in controlling all movement disorders.Specifically, stimulation of the ventral intermediate nucleus of thethalamus appears to be very effective in the treatment of tremor, notonly in patients having Parkinson's disease but also in patients withessential tremor. Lozano. Arch. Med. Res. 2000, 31(3):266–269; Kiss etal., Neuroscience, 2002, 113(1):137–143. Stereotactic thalamotomy hasbeen used in selective cases to treat Parkinson's disease as well asessential tremor. Balas et al., Rev. Neurol. 2001, 32(6):520–524. Thesefindings suggest that the neurologic substrate necessary for thegeneration of tremor in Parkinson's disease and essential tremor may besimilar, and the present inventor fully anticipates them to respond tothe same treatment. Moreover, the observational evidence adduced by thepresent inventor that the present treatment is effective for focaldystonias, such as writer's cramp, supports the notion that the presentinvention is effective for the treatment of all movement disorders,whether associated with a disease such as Parkinson's or essentialtremor, or one of unknown, or idiopathic origin.

EXAMPLES

The features and advantages of the invention are more fully shown by thefollowing non-limiting examples.

Example 1 Synthesis of MMMDPB

A reactor was charged with chlorobenzene (15 ml), and stirring and an N₂flow were started. N,N′-bismethoxymethyl barbituric acid (1.84 g) wasadded to the reactor. The mixture was stirred for 10 minutes and thenheated up to 55–60° C. The mixture was stirred for another 10 minutes.Aluminum chloride (AlCl₃, 0.66 g) was added. The mixture was stirred for10 minutes at about 60° C. The mixture was heated up to 100–110° C. andstirred for another 10 minutes. The mixture was cooled to 60° C. The N₂flow was stopped. A cold solution of hydrochloric acid (32%, 0.5 ml) indeionized water (30 ml) was added. The mixture was stirred at 5° C. forabout 30 minutes. The suspension was filtered, and the filter cake waswashed with cold chlorobenzene (2 ml). The filtrate from the washing wasadded to the filtrate from the filtration. The chlorobenzene (lower)phase was separated. The majority of chlorobenzene from the lower phasewas allowed to evaporate. The resulting residue was diluted with ethylacetate (10 ml). The solution was extracted with 0.5 N sodium hydroxide(15 ml), while maintaining the temperature of the solution at 20° C. orlower. The ethyl acetate phase was washed with cold deionized water (15ml). Water was added to the basic extract. The extract was acidifiedwith a hydrochloric acid solution (32%, 1 ml), while maintaining itstemperature below 20° C. The mixture was stirred for 30 minutes. Thesuspension was then filtered. The filter cake was washed with deionizedwater (5 ml) to yield crude MMMDPB.

The crude product was purified as follows. A second reactor was chargedwith ethanol (95%, 4.5 ml). Stirring was started. The crude MMMDPB (0.87g) was added to the reactor. The mixture was heated up to 60° C. andstirred for about 30 minutes. The mixture was cooled to room temperatureand stirred for about 30 minutes. The resulting suspension was filtered.The filter cake was washed with ethanol (95%, 1 ml). The wet product wasdried in a vacuum oven at 60° C. for about 10 hours.

Example 2 Treatment of Essential Tremor in a Phase II Double-Blind Study

Twelve patients were selected using criteria for definite essentialtremor as classified by the National Institute of Health (NIH)Diagnostic Criteria for Essential Tremor and the Tremor InvestigationGroup (TRIG) Proposed Criteria for Diagnosing Essential Tremor. SeeJankovic J. Essential Tremor: Clinical Characteristics, Neurology,20000:54 (Suppl 4); S21–25, incorporated by reference in its entirety.According to these protocols, patients must have bilateral posturaltremor of both upper extremities with an amplitude rating of 2 orgreater in one arm and 1 or greater in the other, which is visible,persistent, and longstanding (preferably>3 years). Patients were taperedoff medications and vitamins, energy drinks, grapefruit and supplements7 days prior to the commencement of the study. They were instructed tostop tremor medications 14 days prior to study commencement, aftertaper. There were some dietary restrictions:

The patients were randomized to receive with DMMDPB, 400 mg twice dailyin the morning and evening (12 hours apart, total daily dose 800 mg) orplacebo (9 patients on drugs, 3 on placebo) for 14 days. Patients wereconfined one day prior to dosing and for the initial two days of dosingfor the baseline neurological assessment. Evaluations of tremor wereconducted on days 0, 1, 2, 4, 6, 8, 10, 12, 14, 15, 16, 18, 20 and atleast 2 weeks after termination of treatment using established ratingmethods. See Fahn S. et al., Clinical rating scale for tremor, In:Parkinson's Disease and Movement Disorders, Jancovic J., Tolosa E.(Eds.) 1998 Urban & Swarzenberg, Inc. Baltimore, Md., USA 225–34.Concurrent plasma concentrations of DMMDPB were measured. Blood sampleswere collected on days 1, 2, 4, 6, 8, 10, 12, 14 and during morningvisits on days 16, 18, 20, 22 and at 2, 4, 8 and 12 hours past the trialadministration. Adverse events were also assessed.

Evaluations of tremor were conducted with at least one of a clinicalrating scale, a patient-reported disability/symptom scale, andneurophysiological measurements, such as accelerometric recordings.Since the correlation between accelerometry scores and functionaldisability scores has been subject to criticism in the literature,clinical grading scales and patient reporting were used as the primaryparameters.

On unblinding, patients 2–4, 6–9 and 11 were treated and patients 1, 5and 10 were on placebo. As can be seen from Table 1, five of the ninetreated patients showed improvement greater than 50% compared tobaseline after treatment with DMMDBP for 14 days. Placebo patientsexhibited less than 50% improvement. The level of improvement shown inthe drug-treated patients was statistically significant (p<0.02) byone-tail t test.

TABLE 1 Drug Response (C − B) (D − B) Avg. of Absolute Overall (D − C)Baseline Avg. of days 6, 8, First First Change Second Second Scoredays/1, 2, 4 10, 12, 14 Period Period % @ 14 Overall % Period Period %Subject# “B” “C” “D” Change Change days Change Difference Change 9 31.011.3 6.8 (19.7) −64% (24.2) −78% (4.5) −40% 3 33.0 15.7 9.5 (17.3) −52%(23.5) −71% (6.2) −39% 7 20.0 10.7 6.2 (9.3) −47% (13.8) −69% (4.5) −42%4 25.0 18.3 15.2 (6.7) −27% (9.8) −39% (3.1) −17% 6 17.0 10.7 9.8 (6.3)−37% (7.2) −42% (0.9)  −8% 11 16.0 9.7 9.2 (6.3) −39% (6.8) −43% (0.5) −5% 8 21.0 15.0 9.2 (6.0) −29% (11.8) −56% (5.8) −39% 2 24.0 18.7 11.8(5.3) −22% (12.2) −51% (6.9) −37% 10 14.0 9.0 8.0 (5.0) −36% (6.0) −43%(1.0) −11% 1 17.0 14.0 13.8 (3.0) −18% (3.2) −19% (0.2)  −1% 12 22.019.0 13.8 (3.0) −14% (8.2) −37% (5.2) −27% 5 22.0 20.7 13.8 (1.3)  −6%(8.2) −37% (6.9) −33%

The mean absolute change in baseline tremor score and plasmaconcentrations of DMMDBP, MMMDPB, and DPB is shown in Table 2, and FIG.1.

TABLE 2 Absolute Change in Baseline Time Tremor Score PlasmaConcentration (μg/ml) Days Hours Placebo Drug DMMDPB MMMDPB DPB 1 0 0 00.00 0.00 0.00 1 1 ND ND 0.03 0.21 0.11 1 2 ND ND 0.19 0.71 0.29 1 4 NDND 0.33 1.73 0.97 1 8 ND ND 0.11 1.27 1.44 1 12 −5 −10 0.10 1.22 1.78 236 −3 −12 0.42 4.96 3.72 4 84 −7 −14 0.50 11.50 9.11 6 132 −8 −16 0.3714.54 14.67 8 180 −8 −17 0.33 17.61 21.23 10 228 −7 −18 0.27 18.27 25.6212 276 −7 −19 0.22 17.96 30.13 14 324 −9 −18 0.19 16.21 33.90 16 372 −7−11 0.07 9.12 32.74 18 420 −6 −5 0.03 5.43 25.70 20 468 −3 −3 0.03 1.3714.13 22 516 −9 −3 0.02 0.31 7.68 24 684 −7 −6 ND ND ND ND = NotDetermined

The mean absolute change in baseline tremor score vs. plasmaconcentrations of MMDPB and DPB after multiple oral doses of DMMDPB inpatients with essential tremor is shown in FIG. 2.

Table 3 shows a comparison of the mean change in tremor score frombaseline (Day-1) to a composite endpoint (average of Days 12 and 14)between those patients treated with the drug (DMMDBP) and those treatedwith a placebo. The mean absolute change in the treated group was 18.3as compared to 8.0 in the placebo group. This difference isstatistically significant using a 2-tailed Student's t-test forindependent groups (p=0.05).

TABLE 3 Baseline Tremor Absolute Change Score From Baseline Treatment N(Day - 1) Tremor Score (Day - 1) P Value¹ Placebo 3 25.0 −8.0 0.05 Drug8 32.0 −18.3 N is the number of patients in the group. ¹Patient'st-test, treated vs. placebo, 2-tailed

Table 4 shows a comparison of the linear trends in tremor score frombaseline (Day 0) to a single endpoint (Day 14) between the group ofpatients treated with the drug (DMMDBP) and the group of patients givena placebo. All the data points between Day 0 and Day 14 were used inthis analysis. The respective baseline and Day 14 performance scoreswere 32.0 and 13.9 in the treated group as compared to 25.0 and 16.0 inthe placebo group. The treated and placebo performance score lineartrends from Day 0 to Day 14 were found to differ significantly using a2-factor mixed ANOVA model followed by a 1-tailed F-test for comparisonof linear trends (p=0.05). In using this repeated measures statisticalapproach, the linear trends were observed within subject, with betweensubject effects being filtered out.

TABLE 4 Baseline Tremor Absolute Change Score From Baseline Treatment N(Day - 1) Tremor Score (Day - 1) P Value¹ Placebo 3 25.0 16.0 0.05 Drug8 32.0 13.9 N is the number of patients in that treatment group.¹Difference in linear trend, treated vs. placebo, 1-tailed.

Example 3 Treatment of Parkinson's Disease

Patients with treated, symptomatic Parkinson's disease are oftentroubled by tremor, by dystonia and chorea movements (dyskinesias)secondary to dopaminergic agents and by prominent motor fluctuationsthroughout the day (“wearing-off” or “on-off”). In addition, Parkinson'sdisease may sometimes have some intrinsic dystonic features. All ofthese tremor features may potentially be alleviated by treatment withT2000 or related compounds.

We will select 25 patients having on-off phenomena and 25 patients withtremor (the two groups may partially overlap, i.e., some patients mayexhibit both syndromes). These patients will be treated with from 400 upto 800 mg of DMMDPB orally each day for two to three weeks. Patientswill be monitored every other day to evaluate the degree of reduction intremor and time in the “off” state as indicated using a modification ofthe Unified Parkinson's Disease Rating Scale (UPDRS). Koller, W. C., andTolosa, E., Current and Emerging Drug Therapies in the Management ofParkinson's Disease, 50(6): S1–S48 (1998). It is anticipated that aftertwo weeks of treatment, the treated patients will show a 25–50%reduction in tremor and a greater than about 10% in the time-off stateas evidenced by routine neurologic examination.

Improvement in dyskinesia (dystonia and chorea) will also be assessed.Preliminary observations indicate that dystonic symptoms (e.g., writer'scramp) in patients with essential tremor are alleviated by therapy using450 mg per day of DMMDPB to treat tremor. It is thus anticipated thatthe aforementioned regime will show effectiveness in dystonia and moregenerally dyskinesia of patients with Parkinson's disease.

Example 4 Treatment of Essential Tremor with a PhosphonooxymethylDerivative

Twenty patients will be selected using criteria for definite essentialtremor as classified by the National Institute of Health (NIH)Diagnostic Criteria for Essential Tremor and the Tremor InvestigationGroup (TRIG) Proposed Criteria for Diagnosing Essential Tremor. SeeJankovic J. Essential Tremor: Clinical Characteristics, Neurology,20000:54 (Suppl 4); S21–25, incorporated by reference in its entirety.According to these protocols, patients must have bilateral posturaltremor of both upper extremities with an amplitude rating of 2 orgreater in one arm and 1 or greater in the other, which is visible,persistent, and longstanding (preferably>3 years). Patients will betapered off medications and vitamins, energy drinks, grapefruit andsupplements 7 days prior to the commencement of the study. They will beinstructed to stop tremor medications 14 days prior to studycommencement, after taper.

The patients will be randomized to receive phosphonooxymethylderivatives, 400 mg twice daily in the morning and evening (12 hoursapart, total daily dose 800 mg) or placebo (9 patients on drugs, 3 onplacebo) for 14 days. Patients will be confined one day prior to dosingand for the initial two days of dosing for the baseline neurologicalassessment. Evaluations of tremor will be conducted on days 0, 1, 2, 4,6, 8, 10, 12, 14, 15, 16, 18, 20 and at least 2 weeks after terminationof treatment using established rating methods. See Fahn S. et al.,Clinical rating scale for tremor, In: Parkinson's Disease and MovementDisorders, Jancovic J., Tolosa E. (Eds.) 1998 Urban & Swarzenberg, Inc.Baltimore, Md., USA 225–34. Concurrent plasma concentrations ofphosphonooxymethyl derivatives, MMMDPB and DPB will be measured. Bloodsamples will be collected on days 1, 2, 4, 6, 8, 10, 12, 14 and duringmorning visits on days 16, 18, 20, 22 and at 2, 4, 8 and 12 hours pastthe trial administration.

Evaluations of tremor will be conducted with at least one of a clinicalrating scale, a patient-reported disability/symptom scale, andneurophysiological measurements, such as accelerometric recordings.Since the correlation between accelerometry scores and functionaldisability scores has been subject to criticism in the literature,clinical grading scales and patient reporting will be used as theprimary parameters. On unblinding, we expect that patients treated withphosphonooxymethyl derivatives will have shown a significantly decreasedtremor as opposed to patients treated with placebo.

The embodiments illustrated and discussed in this specification areintended only to teach those skilled in the art the best way known tothe inventors to make and use the invention. Nothing in thisspecification should be considered as limiting the scope of the presentinvention. Modifications and variation of the above-describedembodiments of the invention are possible without departing from theinvention, as appreciated by those skilled in the art in light of theabove teachings. It is therefore understood that, within the scope ofthe claims and their equivalents, the invention may be practicedotherwise than as specifically described.

All patents, applications, publications, test methods, literature, andother materials cited herein are hereby incorporated by reference.

1. A method of treating essential tremor comprising administering to asubject in need of treatment a composition comprising a therapeuticallyeffective amount of a compound according to the following formula:

or a pharmaceutically acceptable salt, prodrug or metabolite thereof. 2.A method of treating essential tremor comprising administering to asubject in need of treatment a composition comprising a therapeuticallyeffective amount of a compound according to the following formula:

or a pharmaceutically acceptable salt, prodrug or metabolite thereof. 3.A method of treating essential tremor comprising administering to asubject in need of treatment a composition comprising a therapeuticallyeffective amount of a compound according to the following formula:

or a pharmaceutically acceptable salt, prodrug or metabolite thereof. 4.A method of treating Parkinson's disease comprising administering to asubject in need of treatment a composition comprising a therapeuticallyeffective amount of a compound according to the following formula:

or a pharmaceutically acceptable salt, prodrug or metabolite thereof. 5.A method of treating Parkinson's disease comprising administering to asubject in need of treatment a composition comprising a therapeuticallyeffective amount of a compound according to the following formula:

or a pharmaceutically acceptable salt, prodrug or metabolite thereof. 6.A method of treating Parkinson's disease comprising administering to asubject in need of treatment a composition comprising a therapeuticallyeffective amount of a compound according to the following formula:

or a pharmaceutically acceptable salt, prodrug or metabolite thereof. 7.The method of claim 2, wherein the composition comprises apharmaceutically acceptable salt of the compound.
 8. The method of claim7, wherein the pharmaceutically acceptable salt comprises a sodium salt.9. The method of claim 3, wherein the composition comprises apharmaceutically acceptable salt of the compound.
 10. The method ofclaim 9, wherein the pharmaceutically acceptable salt comprises a sodiumsalt.
 11. The method of claim 5, wherein the composition comprises apharmaceutically acceptable salt of the compound.
 12. The method ofclaim 11, wherein the pharmaceutically acceptable salt comprises asodium salt.
 13. The method of claim 6, wherein the compositioncomprises a pharmaceutically acceptable salt of the compound.
 14. Themethod of claim 13, wherein the pharmaceutically acceptable saltcomprises a sodium salt.